Researchers mapped how different endocannabinoid enzyme inhibitors affect brain levels of anandamide and 2-AG in living animals, revealing important species differences between rats and mice.
Read this if you follow endocannabinoid research and want to understand the pharmacological tools being used.
JZL184 boosted 2-AG in mice but not in rats, revealing a critical species difference
What the researchers found
Using microdialysis to measure endocannabinoid levels in the nucleus accumbens of living animals, researchers characterized six commonly used research compounds. FAAH inhibitors (URB597, PF-3845) selectively increased anandamide during neural activity without affecting 2-AG. The MAGL inhibitor URB602 increased 2-AG without affecting anandamide.
A key finding was a species difference: JZL184, a widely used MAGL inhibitor, effectively boosted 2-AG in mice but not in rats. The dual FAAH/MAGL inhibitor JZL195 increased both endocannabinoids in both species. These species differences have important implications for interpreting prior research.
Why it matters
Understanding exactly how research tools affect endocannabinoid levels in living brains is critical for interpreting cannabinoid research and developing medicines. The species difference for JZL184 means that findings from mouse studies using this compound may not directly apply to rats or humans.
The numbers in context
6 compounds tested. PF-3845 and URB597 selectively increased anandamide. URB602 selectively increased 2-AG. JZL184 worked in mice but not rats. JZL195 increased both in both species. AM404 modestly increased 2-AG. UCM707 had no effect on either.
How the study worked
In vivo microdialysis in the nucleus accumbens of rats and mice. Potassium-induced depolarization was used to stimulate endocannabinoid release. Six compounds were tested: AM404 and UCM707 (transport inhibitors), URB597 and PF-3845 (FAAH inhibitors), URB602 (MAGL inhibitor), JZL184 (MAGL inhibitor), and JZL195 (dual FAAH/MAGL inhibitor).
What this study cannot tell us
Microdialysis measures extracellular levels, which may not perfectly reflect synaptic concentrations. The nucleus accumbens was the only brain region studied; effects may differ in other areas. The compounds were tested under stimulated conditions, which may not reflect baseline endocannabinoid regulation.
How to read the evidence
Rigorous pharmacological characterization study in two species; methodologically strong but narrow in scope.
When this study was published
Published in 2012. These pharmacological tools and the species differences identified remain relevant to current endocannabinoid research.
The bigger picture
This pharmacological characterization study is foundational for the field. As researchers develop endocannabinoid-based therapeutics, knowing exactly which tool does what, and in which species, prevents misinterpretation of results and guides the choice of compounds for clinical development.
Questions still open
- Do these species differences extend to humans? Would combining selective FAAH and MAGL inhibitors produce different effects than a dual inhibitor? Which endocannabinoid pathway (anandamide vs. 2-AG) is more therapeutically relevant for different conditions?
Common questions
What are anandamide and 2-AG?
Why do species differences matter?
Read the original research
Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.
ACS chemical neuroscience, 3(5), 407-17
Citation
Wiskerke, Joost; Irimia, Cristina; Cravatt, Benjamin F; De Vries, Taco J; Schoffelmeer, Anton N M; Pattij, Tommy; Parsons, Loren H. (2012). Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.. ACS chemical neuroscience, 3(5), 407-17. https://doi.org/10.1021/cn300036b
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